M-HOF-Opt: Multi-Objective Hierarchical Output Feedback Optimization via Multiplier Induced Loss Landscape Scheduling

We address the online combinatorial choice of weight multipliers for multi-objective optimization of many loss terms parameterized by neural works via a probabilistic graphical model (PGM) for the joint model parameter and multiplier evolution process, with a hypervolume based likelihood promoting multi-objective descent. The corresponding parameter and multiplier estimation as a sequential decision process is then cast into an optimal control problem, where the multi-objective descent goal is dispatched hierarchically into a series of constraint optimization sub-problems. The subproblem constraint automatically adapts itself according to Pareto dominance and serves as the setpoint for the low level multiplier controller to schedule loss landscapes via output feedback of each loss term. Our method is multiplier-free and operates at the timescale of epochs, thus saves tremendous computational resources compared to full training cycle multiplier tuning. It also circumvents the excessive memory requirements and heavy computational burden of existing multi-objective deep learning methods. We applied it to domain invariant variational auto-encoding with 6 loss terms on the PACS domain generalization task, and observed robust performance across a range of controller hyperparameters, as well as different multiplier initial conditions, outperforming other multiplier scheduling methods. We offered modular implementation of our method, admitting extension to custom definition of many loss terms

The impact of a reduced dose of dexamethasone on glucose control after coronary artery bypass surgery

<p>Abstract</p> <p>Background</p> <p>Intensive insulin therapy to maintain normoglycemia after cardiac surgery reduces morbidity and mortality. We investigated the magnitude and duration of hyperglycemia caused by dexamethasone administered after cardiopulmonary bypass.</p> <p>Methods</p> <p>A single-center before-after cohort study was performed. All consecutive patients undergoing coronary artery bypass grafting with cardiopulmonary bypass during a 6-month period were included. Insulin administration was guided by a sliding scale protocol. Halfway the observation period, the dexamethasone protocol was changed. The single dose (1D) group received a pre-operative dose of dexamethasone of 1 mg/kg. The double dose group (2D) received an additional dose of 0.5 mg/kg of dexamethasone post-operatively at ICU admission.</p> <p>Results</p> <p>We included 116 patients in the 1D group and 158 patients in the 2D group. There were no significant baseline differences between the groups. Median Euroscore was 5. In univariable analysis, the glucose level was different between groups 1D and 2D at 4, 6, 9, 12 and 24 hours after ICU admission (all p < 0.001). Insulin infusion was higher in the 1D group. Corrected for insulin dose in multivariable linear analysis, the difference in glucose between the 1D and 2D groups was 1.5 mmol/L (95% confidence interval 1.0–2.0, p < 0.001) 12 hours after ICU admission.</p> <p>Conclusion</p> <p>Dexamethasone exerts a hyperglycemic effect in cardiac surgery patients. Patients receiving high-dose corticosteroid therapy should be monitored and treated more intensively for hyperglycemic episodes.</p

Three-Dimensional Biomechanical Analysis of Rearfoot and Forefoot Running

Background: In the running community, a forefoot strike (FFS) pattern is increasingly preferred compared with a rearfoot strike (RFS) pattern. However, it has not been fully understood which strike pattern may better reduce adverse joint forces within the different joints of the lower extremity. Purpose: To analyze the 3-dimensional (3D) stress pattern in the ankle, knee, and hip joint in runners with either a FFS or RFS pattern. Study Design: Descriptive laboratory study. Methods: In 22 runners (11 habitual rearfoot strikers, 11 habitual forefoot strikers), RFS and FFS patterns were compared at 3.0 m/s (6.7 mph) on a treadmill with integrated force plates and a 3D motion capture analysis system. This combined analysis allowed characterization of the 3D biomechanical forces differentiated for the ankle, knee, and hip joint. The maximum peak force (MPF) and maximum loading rate (LR) were determined in their 3 ordinal components: vertical, anterior-posterior (AP), and medial-lateral (ML). Results: For both strike patterns, the vertical components of the MPF and LR were significantly greater than their AP or ML components. In the vertical axis, FFS was generally associated with a greater MPF but significantly lower LR in all 3 joints. The AP components of MPF and LR were significantly lower for FFS in the knee joint but significantly greater in the ankle and hip joints. The ML components of MPF and LR tended to be greater for FFS but mostly did not reach a level of significance. Conclusion: FFS and RFS were associated with different 3D stress patterns in the ankle, knee, and hip joint, although there was no global advantage of one strike pattern over the other. The multimodal individual assessment for the different anatomic regions demonstrated that FFS seems favorable for patients with unstable knee joints in the AP axis and RFS may be recommended for runners with unstable ankle joints. Clinical Relevance: Different strike patterns show different 3D stress in joints of the lower extremity. Due to either rehabilitation after injuries or training in running sports, rearfoot or forefoot running should be preferred to prevent further damage or injuries caused by inadequate biomechanical load. Runners with a history of knee joint injuries may benefit from FFS whereas RFS may be favorable for runners with a history of ankle joint injuries

Implementation and evaluation of a nurse-centered computerized potassium regulation protocol in the intensive care unit - a before and after analysis

<p>Abstract</p> <p>Background</p> <p>Potassium disorders can cause major complications and must be avoided in critically ill patients. Regulation of potassium in the intensive care unit (ICU) requires potassium administration with frequent blood potassium measurements and subsequent adjustments of the amount of potassium administrated. The use of a potassium replacement protocol can improve potassium regulation. For safety and efficiency, computerized protocols appear to be superior over paper protocols. The aim of this study was to evaluate if a computerized potassium regulation protocol in the ICU improved potassium regulation.</p> <p>Methods</p> <p>In our surgical ICU (12 beds) and cardiothoracic ICU (14 beds) at a tertiary academic center, we implemented a nurse-centered computerized potassium protocol integrated with the pre-existent glucose control program called GRIP (Glucose Regulation in Intensive Care patients). Before implementation of the computerized protocol, potassium replacement was physician-driven. Potassium was delivered continuously either by central venous catheter or by gastric, duodenal or jejunal tube. After every potassium measurement, nurses received a recommendation for the potassium administration rate and the time to the next measurement. In this before-after study we evaluated potassium regulation with GRIP. The attitude of the nursing staff towards potassium regulation with computer support was measured with questionnaires.</p> <p>Results</p> <p>The patient cohort consisted of 775 patients before and 1435 after the implementation of computerized potassium control. The number of patients with hypokalemia (<3.5 mmol/L) and hyperkalemia (>5.0 mmol/L) were recorded, as well as the time course of potassium levels after ICU admission. The incidence of hypokalemia and hyperkalemia was calculated. Median potassium-levels were similar in both study periods, but the level of potassium control improved: the incidence of hypokalemia decreased from 2.4% to 1.7% (P < 0.001) and hyperkalemia from 7.4% to 4.8% (P < 0.001). Nurses indicated that they considered computerized potassium control an improvement over previous practice.</p> <p>Conclusions</p> <p>Computerized potassium control, integrated with the nurse-centered GRIP program for glucose regulation, is effective and reduces the prevalence of hypo- and hyperkalemia in the ICU compared with physician-driven potassium regulation.</p

Mutational processes contributing to the development of multiple myeloma.

To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes-aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity-characterize MM. These mutational signatures show evidence of subgroup specificity-APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Three-Dimensional Biomechanical Analysis of Rearfoot and Forefoot Running

Background: In the running community, a forefoot strike (FFS) pattern is increasingly preferred compared with a rearfoot strike (RFS) pattern. However, it has not been fully understood which strike pattern may better reduce adverse joint forces within the different joints of the lower extremity. Purpose: To analyze the 3-dimensional (3D) stress pattern in the ankle, knee, and hip joint in runners with either a FFS or RFS pattern. Study Design: Descriptive laboratory study. Methods: In 22 runners (11 habitual rearfoot strikers, 11 habitual forefoot strikers), RFS and FFS patterns were compared at 3.0 m/s (6.7 mph) on a treadmill with integrated force plates and a 3D motion capture analysis system. This combined analysis allowed characterization of the 3D biomechanical forces differentiated for the ankle, knee, and hip joint. The maximum peak force (MPF) and maximum loading rate (LR) were determined in their 3 ordinal components: vertical, anterior-posterior (AP), and medial-lateral (ML). Results: For both strike patterns, the vertical components of the MPF and LR were significantly greater than their AP or ML components. In the vertical axis, FFS was generally associated with a greater MPF but significantly lower LR in all 3 joints. The AP components of MPF and LR were significantly lower for FFS in the knee joint but significantly greater in the ankle and hip joints. The ML components of MPF and LR tended to be greater for FFS but mostly did not reach a level of significance. Conclusion: FFS and RFS were associated with different 3D stress patterns in the ankle, knee, and hip joint, although there was no global advantage of one strike pattern over the other. The multimodal individual assessment for the different anatomic regions demonstrated that FFS seems favorable for patients with unstable knee joints in the AP axis and RFS may be recommended for runners with unstable ankle joints. Clinical Relevance: Different strike patterns show different 3D stress in joints of the lower extremity. Due to either rehabilitation after injuries or training in running sports, rearfoot or forefoot running should be preferred to prevent further damage or injuries caused by inadequate biomechanical load. Runners with a history of knee joint injuries may benefit from FFS whereas RFS may be favorable for runners with a history of ankle joint injuries

mvTCR - trained models

&lt;p&gt;The zip directory contains the trained models used in the publication &quot;Multimodal learning to integrate single-cell T-cell receptor and transcriptome&quot; (formerly &quot;Integrating T-cell receptor and transcriptome for large-scale single-cell immune profiling analysis &quot;). The full code to reproduce the results of the publication can be found at https://github.com/SchubertLab/mvTCR_reproducibility&lt;/p&gt; &lt;p&gt;&nbsp;&lt;/p&gt